There are two major arms of this project at the present time: (1) the identification and characterization of genes involved in the human metaphyseal dysplasias, including Schmid type, Jansen type and McKusick type metaphyseal dysplasia, as well as the spondyloepi-metaphyseal dysplasias, and (2) clinical description and natural history of these phenotypes, with a particular interest in the relationship between specific mutations and their clinical manifestations. Previous work in our laboratory has shown that mutations in type X collagen (encoded by COL10A1) cause the Schmid type of metaphyseal dysplasia. To date, we and others have found a total of 11 mutations in COL10A1 in the DNA from patients with Schmid type metaphyseal dysplasia. All of these are clustered in the carboxy-terminal domain of type X collagen, suggesting that they may be functional null mutations. This may account for the relatively mild phenotype observed in the Schmid type of metaphyseal dysplasia. Experiments win other laboratories have shown that mutations of COL10A1 affecting the collagenous region of the molecule have much more serious phenotypic consequences in mice. Studies are ongoing in our laboratory to try to find such mutations in human patients with more severe skeletal involvement. For several years we have been collaborating with colleagues at the University of Helsinki, Finland, in a n effort to find the gene causing the McKusick type fo metaphyseal dysplasia, also called cartilage hair hypoplasia, or CHH. An intensive effort to ascertain 11 cases of this disorder among the Amish was undertaken in 1989 and 1990, and those samples are now being used to refine the localization of the CHH gene using linkage disequilibrium methods and positional cloning.